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Thomas Schreiter, Robert K. Gieseler, Ramiro Vílchez-Vargas, Ruy Jauregui, Jan-Peter Sowa, Susanne Klein-Scory, Ruth Bröring, Roland Croner, Jürgen Walter Treckmann, Alexander Link, Ali E. Canbay

• A transcriptome-wide analysis of human liver for demonstrating differences between young and old humans has not yet been performed. However, identifying major age-related alterations in hepatic gene expression may pinpoint ontogenetic shifts with important hepatic and systemic consequences, provide novel pharmacogenetic information, offer clues to efficiently counteract symptoms of old age, and improve the overarching understanding of individual decline. Next-generation sequencing (NGS) data analyzed by the Mann–Whitney nonparametric test and Ensemble Feature Selection (EFS) bioinformatics identified 44 transcripts among 60,617 total and 19,986 protein-encoding transcripts that significantly (\(\it p\) = 0.0003 to 0.0464) and strikingly (EFS score > 0.3:16 transcripts; EFS score > 0.2:28 transcripts) differ between young and old livers. Most of these age-related transcripts were assigned to the categories "regulome", "inflammaging", "regeneration", and "pharmacogenes". NGS results were confirmed by quantitative real-time polymerase chain reaction. Our results have important implications for the areas of ontogeny/aging and the age-dependent increase in major liver diseases. Finally, we present a broadly substantiated and testable hypothesis on a genetically governed "aging cascade!, wherein \(\it PPP1R10\) acts as a putative ontogenetic master regulator, prominently flanked by \(\it IGFALS\) and \(\it DUSP1\). This transcriptome-wide analysis of human liver offers potential clues towards developing safer and improved therapeutic interventions against major liver diseases and increased insights into key mechanisms underlying aging.